Extracellular vesicle–encapsulated IL-10 as novel nanotherapeutics against ischemic AKI

Tang, Tao-Tao; Wang, Bin; Wu, Min; Li, Zuo‐Lin; Feng, Yan; Cao, Jun; Yin, Di; Liu, Hong; Tang, Ri‐Ning; Crowley, Steven D.; Lv, Lin‐Li; Liu, Bi‐Cheng

doi:10.1126/sciadv.aaz0748

Cited by 174 publications

(153 citation statements)

References 43 publications

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“…To obtain labeled MSC-exos, the donor hucMSCs were incubated with 1,1'-dioctadecyl-3,3,3',3'-tetramethylindodicarbocyanine perchlorate (DiD; Invitrogen) or 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate (DiI; Invitrogen) and washed twice with sterile PBS to remove excess dye. After being cultured in FBS-free media for 48 h, the supernatants were used to isolate DiD-labeled MSC-exos or DiI-labeled MSC-exos in the same procedure as above 23 . In this way, the free dye could be removed to the utmost extent.…”

Section: Methodsmentioning

confidence: 99%

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Exosomal miR-125b-5p deriving from mesenchymal stem cells promotes tubular repair by suppression of p53 in ischemic acute kidney injury

et al. 2021

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Mesenchymal stem cells-derived exosomes (MSC-exos) have attracted great interest as a cell-free therapy for acute kidney injury (AKI). However, the in vivo biodistribution of MSC-exos in ischemic AKI has not been established. The potential of MSC-exos in promoting tubular repair and the underlying mechanisms remain largely unknown. Methods: Transmission electron microscopy, nanoparticle tracking analysis, and western blotting were used to characterize the properties of human umbilical cord mesenchymal stem cells (hucMSCs) derived exosomes. The biodistribution of MSC-exos in murine ischemia/reperfusion (I/R) induced AKI was imaged by the IVIS spectrum imaging system. The therapeutic efficacy of MSC-exos was investigated in renal I/R injury. The cell cycle arrest, proliferation and apoptosis of tubular epithelial cells (TECs) were evaluated in vivo and in HK-2 cells. The exosomal miRNAs of MSC-exos were profiled by high-throughput miRNA sequencing. One of the most enriched miRNA in MSC-exos was knockdown by transfecting miRNA inhibitor to hucMSCs. Then we investigated whether this candidate miRNA was involved in MSC-exos-mediated tubular repair. Results: Ex vivo imaging showed that MSC-exos was efficiently homing to the ischemic kidney and predominantly accumulated in proximal tubules by virtue of the VLA-4 and LFA-1 on MSC-exos surface. MSC-exos alleviated murine ischemic AKI and decreased the renal tubules injury in a dose-dependent manner. Furthermore, MSC-exos significantly attenuated the cell cycle arrest and apoptosis of TECs both in vivo and in vitro . Mechanistically, miR-125b-5p, which was highly enriched in MSC-exos, repressed the protein expression of p53 in TECs, leading to not only the up-regulation of CDK1 and Cyclin B1 to rescue G2/M arrest, but also the modulation of Bcl-2 and Bax to inhibit TEC apoptosis. Finally, inhibiting miR-125b-5p could mitigate the protective effects of MSC-exos in I/R mice. Conclusion: MSC-exos exhibit preferential tropism to injured kidney and localize to proximal tubules in ischemic AKI. We demonstrate that MSC-exos ameliorate ischemic AKI and promote tubular repair by targeting the cell cycle arrest and apoptosis of TECs through miR-125b-5p/p53 pathway. This study provides a novel insight into the role of MSC-exos in renal tubule repair and highlights the potential of MSC-exos as a promising therapeutic strategy for AKI.

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Section: Methodsmentioning

confidence: 99%

“…Kidneys were harvested from control, I/R, or MSC-exos-treated mice, and the TECs were isolated by differential sieving as previously described 23 , 31 . Briefly, kidneys were removed and put into cold DMEM/F12 medium.…”

Section: Methodsmentioning

confidence: 99%

Exosomal miR-125b-5p deriving from mesenchymal stem cells promotes tubular repair by suppression of p53 in ischemic acute kidney injury

et al. 2021

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“…Angiogenesis is tightly coupled with bone formation and regeneration for proper bone homeostasis ( Hui et al, 2014 ; Kusumbe et al, 2014 ; Yang et al, 2017 ). Recently, extracellular vesicles (EVs), such as exosomes and microvesicles, have been attracting a strong research interest for use as natural drug delivery systems ( Chen et al, 2018 ; Tang and Wang, 2020 ). Mesenchymal stem cell (MSC)-derived exosomes have been reported to be involved in multiple physiology and pathology activities including osteogenesis, bone regeneration, osteoarthritis, cardiomyoblast hypoxia–reperfusion, cognitive impairment, inflammation, stroke, sepsis, and tumorigenesis ( Zheng et al, 2018 ; Huang et al, 2020 ; Jin et al, 2020 ; Nakano et al, 2020 ; Tan et al, 2020 ; Venkat et al, 2020 ; Xu et al, 2020 ; Zou et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

BMSC-Derived Exosomal miR-29a Promotes Angiogenesis and Osteogenesis

Peng

Liu

et al. 2020

Front. Cell Dev. Biol.

123

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Angiogenesis and osteogenesis are tightly coupled during bone modeling and remodeling processes. Here we reported that bone marrow mesenchymal stem cell (BMSC)-derived exosomal miR-29a promotes angiogenesis and osteogenesis in vitro and in vivo. BMSC-derived exosomes (BMSCs-Exos) can be taken up by human umbilical vein endothelial cells (HUVECs) and promote the proliferation, migration, and tube formation of HUVECs. MiRNA-29a level was high in BMSCs-Exos and can be transported into HUVECs to regulate angiogenesis. VASH1 was identified as a direct target of miR-29a, mediating the effects of BMSC-derived exosomal miR-29a on angiogenesis. More interestingly, miR29a-loaded exosomes from engineered BMSCs (miR-29a-loaded BMSCs-Exos) showed a robust ability of promoting angiogenesis and osteogenesis in vivo. Taken together, these findings suggest that BMSC-derived exosomal miR-29a regulates angiogenesis and osteogenesis, and miR-29a-loaded BMSCs-Exos may serve as a potential therapeutic target for osteoporosis.

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“…Pathologically, tumor-derived EVs contain abundant TGF-β, promoting tumor progression by enhancing recipient tumor cell migration [ 26 ]. EV-associated cytokines can also be used therapeutically, i.e., IL-10-loaded EVs could significantly attenuate ischemic/reperfusion injury-related renal tubular injury and inflammation [ 27 ]. Clinically, the plasma exosome cytokine profile has been demonstrated to be associated with diseases.…”

Section: Discussionmentioning

confidence: 99%

Cytokine Profile in Plasma Extracellular Vesicles of Parkinson’s Disease and the Association with Cognitive Function

Chan

Chung

Chen

et al. 2021

Cells

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Plasma extracellular vesicles (EVs) containing various molecules, including cytokines, can reflect the intracellular condition and participate in cell-to-cell signaling, thus emerging as biomarkers for Parkinson’s disease (PD). Inflammation may be a crucial risk factor for PD development and progression. The present study investigated the role of plasma EV cytokines as the biomarkers of PD. This cross-sectional study recruited 113 patients with PD, with mild to moderate stage disease, and 48 controls. Plasma EVs were isolated, and the levels of cytokines, including pro-interleukin (IL)-1β, IL-6, IL-10, tumor necrosis factor (TNF)-α, and transforming growth factor (TGF)-β1, were evaluated. Patients with PD had significantly increased plasma EV pro-IL-1β and TNF-α levels compared with controls after adjustment for age and sex. Despite the lack of a significant association between plasma EV cytokines and motor symptom severity in patients with PD, cognitive dysfunction severity, assessed using the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment, was significantly associated with plasma EV pro-IL-1β, IL-6, IL-10, and TNF-α levels. This association was PD specific and not found in controls. Furthermore, patients with PD cognitive deficit (MMSE < 26) exhibited a distinguished EV cytokine profile compared to those without cognitive deficit. The findings support the concept of inflammatory pathogenesis in the development and progression of PD and indicate that plasma EV cytokines may serve as PD biomarkers in future.

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Extracellular vesicle–encapsulated IL-10 as novel nanotherapeutics against ischemic AKI

Cited by 174 publications

References 43 publications

Exosomal miR-125b-5p deriving from mesenchymal stem cells promotes tubular repair by suppression of p53 in ischemic acute kidney injury

Exosomal miR-125b-5p deriving from mesenchymal stem cells promotes tubular repair by suppression of p53 in ischemic acute kidney injury

BMSC-Derived Exosomal miR-29a Promotes Angiogenesis and Osteogenesis

Cytokine Profile in Plasma Extracellular Vesicles of Parkinson’s Disease and the Association with Cognitive Function

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